The overall goal of this proposal is to characterize demand induced ischemia in terms of alterations in metabolism, structure and function in the blood perfused Langendorff. Clinically, demand induced is witnessed daily in patients with coronary artery disease and exertional angina and may exist in regions remote from infarcted tissue in patients with multivessel disease during an acute myocardial infarction. Demand induced ischemia is produced by increasing oxygen demand while maintaining oxygen supply constant and is a previoulsy uncharacterized pathophysiologic model of myocardial ischemia. The blood perfused Langedorff is a recently developed isolated heart preparation with physiologic perfusion and metabolic rates. Characterization of demand induced ischemia will be undertaken by comparing the metabolic, structural and functional alterations observed to those encountered during reduced flow ischemia and normoxic increased work. Specifically, differences in oxygen consumption, glucose and palmitate oxidation, lactate and pyruvate production, myocardial high energy phosphate, glycogen, lactate and pyruvate content in demand induced and reduced flow ischemia will be evaluated and related to the severity of oxygen supply-demand imbalance. Morphologic evidence of ischemia injury following 60 minutes of demand induced ischemia will be sought and compared to results obtained in reduced flow ischemia and normoxic increased work experiments. Because oxidative metabolism is increased in demand induced ischemia relative to reduced flow ischemia, tissue accumulation of acyl-Co and carnitine might be different in the two types of ischemia which could produce differing sensitivities to the deleterious effects of increased perfusate palmitate concentration on ischemia left ventricular performance. A specific protocol is proposed to investigate these possibilities. Finally, the effect of absolute perfusion rate on glucose utilization during reduced flow ischemia will be evaluated in buffer and blood perfused hearts. Completion of these projects will provide and initial characterization of a new, clinically relevant model of myocardial ischemia in a physiologic isolated heart preparation.